Previous preclinical work elucidating the existence of a dopaminergic paracrine system in the rat stomach and pancreas is now leading to studies of the clinical relevance of this peripheral dopaminergic system. Continuing preclinical work is also focussing on the function of this system in the rat digestive tract. Studies in humans showing higher concentrations of dopamine and its metabolites in portal venous than arterial plasma have indicated substantial production of dopamine by tissues of the gastrointestinal tract, amounting up to 45% of the total body dopamine production. Similar to our work in rats, tissue samples from human stomach and the duodenum show immunoreactive tyrosine hydroxylase in non-neuronal cell bodies and detectable levels of tyrosine hydroxylase enzyme activity. Most of the dopamine produced by digestive tissues is unlikely to be derived from sympathetic nerves but appears to reflect production by a novel non-neuronal dopaminergic system. Other findings that most of the sulfate conjugates of dopamine and its metabolites originate from mesenteric organs indicate that measurements of these compounds in plasma or urine provide a means to study clinically the activity of this relatively inaccessible dopaminergic system. This conclusion is supported by work showing 45-fold increases in dopamine-sulfate after meal ingestion. Since dopamine-sulfate is reduced only slightly by a three-day fast it is unlikely that the dopamine-sulfate produced in the digestive tract is formed from elements in the diet but instead reflects the activity of dopaminergic paracrine system in the digestive tract. This system appears to be involved in regulation of gut motility, mucosal blood flow, bicarbonate and exocrine secretions and sodium transport. Parallel preclinical studies utilizing tyrosine hydroxylase enzyme assays and RT-PCR of tyrosine hydroxylase gene products are being carried out to examine the expression and function of tyrosine hydroxylase in non-neuronal cellular elements of the rat digestive tract. In situ peripheral microdialysis combined with local inhibition of aromatic amino acid decarboxylase is also being used to examine changes in rat stomach tyrosine hydroxylase in vivo.